Specific features of ß-catenin-mutated hepatocellular carcinomas

Abstract

CTNNB1, encoding the ß-catenin protein, is a key oncogene contributing to liver carcinogenesis. Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer in adult, representing the third leading cause of cancer-related death. Aberrant activation of the Wnt/ß-catenin pathway, mainly due to mutations of the CTNNB1 gene, is observed in a significant subset of HCC. In this review, we first resume the major recent advances in HCC classification with a focus on CTNNB1-mutated HCC subclass. We present the regulatory mechanisms involved in β-catenin stabilisation, transcriptional activity and binding to partner proteins. We then describe specific phenotypic characteristics of CTNNB1-mutated HCC thanks to their unique gene expression patterns. CTNNB1-mutated HCC constitute a full-fledged subclass of HCC with distinct pathological features such as well-differentiated cells with low proliferation rate, association to cholestasis, metabolic alterations, immune exclusion and invasion. Finally, we discuss therapeutic approaches to target ß-catenin-mutated liver tumours and innovative perspectives for future drug developments.

Fig. 1. Main molecular classes and subclasses of HCC.

a HCC classification and timeline and (b) features. HCC can be divided in two major groups ‘proliferative’ and ‘non-proliferative’. The proliferation group is mainly characterised by high level of AFP, poor survival, poor differentiated-HCC, chromosome instability, HBV infection, mitogenic/stem-cell like properties and an immunogenic phenotype. The non-proliferative group is characterised by low level of AFP, good survival, differentiated-HCC, chromosome stability, hypermethylation, CTNNB1 mutation and an immune suppression profile.

Fig. 2. Involvement of wild-type (WT) and mutated ß-catenin in adhesion and Wnt signalling in HCC.

β-catenin plays a dual role in hepatocytes: mediator of adhesion and key actor of the Wnt/ß-catenin signalling pathway. When β-catenin proteins are mutated, they are stabilised and translocated into the nucleus to play their role of transcriptional co-factor for genes involved in tumour progression. APC, adenomatous polyposis coli protein; βTRCP, beta-transducin repeat containing; E3 ubiquitin protein ligase; BC, bile canaliculi; CK1α, casein kinase 1 isoform-α; DVL, dishevelled; FZD, frizzled; GSK3β, glycogen synthase kinase 3β; LEF, lymphoid enhancer-binding factor; LRP low-density lipoprotein receptor-related protein; TCF T cell factor. Figure designed with BioRender.

Fig. 3. CTNNB1 mutations in HCC and binding partners of the ß-catenin protein.

Mutations of CTNNB1 are mostly found in the exon 3 but two other hotspots are also located in exons 7 and 8. The β-catenin protein has a central region composed of 12 Armadillo repeats that allows the interaction with many other partners. UTR, untranslated region; CDS, coding sequence; CTTA, C-Terminal Transcriptional Activators; APC, adenomatous polyposis coli protein, βTRCP, beta-transducin repeat containing E3 ubiquitin protein ligase; LEF, lymphoid enhancer-binding factor; TCF, T cell factor; FOXO, forkhead box; LRH-1, liver receptor homolog-1; AR, androgen receptor; BCL9, B-cell lymphoma-9; ICAT, inhibitor of β-catenin and Tcf-4; CBP, CREB-binding protein. Inspired from cBioPortal. Figure designed with BioRender.

Fig. 4. Specific features of ß-catenin-mutated HCC.

ß-catenin-mutated HCC display particular intrinsic biological properties. They present a low proliferation rate, important cellular differentiation and chromosome stability. Moreover, these tumours are characterised by cholestasis, metabolic alterations, invasion and capability to escape the immune system. Figure designed with BioRender.